Comparative in silico profiling of epigenetic modifiers in human tissues

The technology of tissue differentiation from human pluripotent stem cells has attracted attention as a useful resource for regenerative medicine, disease modeling and drug development. Recent studies have suggested various key factors and specific culture methods to improve the successful tissue differentiation and efficient generation of human induced pluripotent stem cells. Among these methods, epigenetic regulation and epigenetic signatures are regarded as an important hurdle to overcome during reprogramming and differentiation. Thus, in this study, we developed an in silico epigenetic panel and performed a comparative analysis of epigenetic modifiers in the RNA-seq results of 32 human tissues. We demonstrated that an in silico epigenetic panel can identify epigenetic modifiers in order to overcome epigenetic barriers to tissue-specific differentiation.     

Epigenetic Signatures Associated with Different Levels of Differentiation Potential in Human Stem Cells

Background

The therapeutic use of multipotent stem cells depends on their differentiation potential, which has been shown to be variable for different populations. These differences are likely to be the result of key changes in their epigenetic profiles.

Methodology/Principal Findings

to address this issue, we have investigated the levels of epigenetic regulation in well characterized populations of pluripotent embryonic stem cells (ESC) and multipotent adult stem cells (ASC) at the trancriptome, methylome, histone modification and microRNA levels. Differences in gene expression profiles allowed classification of stem cells into three separate populations including ESC, multipotent adult progenitor cells (MAPC) and mesenchymal stromal cells (MSC). The analysis of the PcG repressive marks, histone modifications and gene promoter methylation of differentiation and pluripotency genes demonstrated that stem cell populations with a wider differentiation potential (ESC and MAPC) showed stronger representation of epigenetic repressive marks in differentiation genes and that this epigenetic signature was progressively lost with restriction of stem cell potential. Our analysis of microRNA established specific microRNA signatures suggesting specific microRNAs involved in regulation of pluripotent and differentiation genes.

Conclusions/Significance

Our study leads us to propose a model where the level of epigenetic regulation, as a combination of DNA methylation and histone modification marks, at differentiation genes defines degrees of differentiation potential from progenitor and multipotent stem cells to pluripotent stem cells.     

X chromosome inactivation in human and mouse pluripotent stem cells

Since the groundbreaking hypothesis of X chromosome inactivation (XCI) proposed by Mary Lyon over 50 years ago, a great amount of knowledge has been gained regarding this essential dosage compensation mechanism in female cells. For the mammalian system, most of the mechanistic studies of XCI have so far been investigated in the mouse model system, but recently, a number of interesting XCI studies have been extended to human pluripotent stem cells, including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Emerging data indicate that XCI in hESCs and hiPSCs is much more complicated than that of their mouse counterparts. XCI in human pluripotent stem cells is not as stable and is subject to environmental influences and epigenetic regulation in vitro. This mini-review highlights the key differences in XCI between mouse and human stem cells with a greater emphasis placed on the understanding of the epigenetic regulation of XCI in human stem cells.     

Epigenetic regulation in adult stem cells and cancers

Adult stem cells maintain tissue homeostasis by their ability to both self-renew and differentiate to distinct cell types. Multiple signaling pathways have been shown to play essential roles as extrinsic cues in maintaining adult stem cell identity and activity. Recent studies also show dynamic regulation by epigenetic mechanisms as intrinsic factors in multiple adult stem cell lineages. Emerging evidence demonstrates intimate crosstalk between these two mechanisms. Misregulation of adult stem cell activity could lead to tumorigenesis, and it has been proposed that cancer stem cells may be responsible for tumor growth and metastasis. However, it is unclear whether cancer stem cells share commonalities with normal adult stem cells. In this review, we will focus on recent discoveries of epigenetic regulation in multiple adult stem cell lineages. We will also discuss how epigenetic mechanisms regulate cancer stem cell activity and probe the common and different features between cancer stem cells and normal adult stem cells.     

RNA结合蛋白在多能干细胞命运转变中的研究进展

RNA结合蛋白(RNA binding proteins,RBPs)是一类通过其RNA结合结构域与RNA相互作用的蛋白质,在细胞内发挥着非常重要的作用。RBPs参与从RNA代谢(包括RNA的可变剪接、稳定性、翻译)到表观遗传修饰等多种调控途径。已有大量文献报道转录因子、表观遗传修饰和细胞外信号通路参与调控干细胞的多能性维持、分化和体细胞重编程,但对于RBPs在细胞命运转变中作用的研究报道甚少。该文主要综述了RBPs通过调控RNA的可变剪接、mRNA稳定性、翻译水平、microRNA代谢及组蛋白修饰进而调控干细胞多能性维持和体细胞重编程。     

表观遗传学与肿瘤干细胞

肿瘤干细胞模型是关于肿瘤形成及生物学特征的一种重要观点。该模型认为肿瘤发生的核心是一群类似于成体干细胞的肿瘤细胞, 具有自我增殖和分化潜能, 称为肿瘤干细胞(Cancer stem cells, CSCs)。目前在多种肿瘤中都发现了CSCs, 其不仅能导致肿瘤发生, 还是引起肿瘤转移、复发、抗药的关键原因。因此, 研究CSC的调控机制具有重要意义。近年来的研究发现, 除了基础的遗传学因素外, 表观遗传学在CSCs的调控中同样具有重要作用。目前主要的表观遗传学机制包括DNA甲基化、组蛋白修饰、染色质重塑及miRNA等, 能有效调节基因表达及细胞表型, 也是肿瘤研究的新热点。文章主要围绕近几年CSCs的特性研究及表观遗传学线索, 阐述表观遗传学机制调控CSCs的最新进展。     

生殖细胞形成的调控机制及体外培养体系的研究进展

生殖细胞是多细胞生物体遗传物质传递的载体,在发育生物学、临床医学及畜牧业生产等领域中具有广阔的应用前景。原始生殖细胞作为胚胎体内最早出现的生殖细胞,在发育过程中受多种信号因子的诱导,发生特化、迁移、分化及减数分裂,最终形成单倍体的配子,此过程在遗传学和表观遗传学方面受到严格的调控。另外,多能性干细胞向生殖细胞的分化以及生殖细胞的体外培养方面在最近均取得了较大的进展。该文将主要围绕原始生殖细胞,综述最近几年来关于生殖细胞形成中的转录调控及体外培养体系的进展。     

The therapeutic potential of stem cells

In recent years, there has been an explosion of interest in stem cells, not just within the scientific and medical communities but also among politicians, religious groups and ethicists. Here, we summarize the different types of stem cells that have been described: their origins in embryonic and adult tissues and their differentiation potential in vivo and in culture. We review some current clinical applications of stem cells, highlighting the problems encountered when going from proof-of-principle in the laboratory to widespread clinical practice. While some of the key genetic and epigenetic factors that determine stem cell properties have been identified, there is still much to be learned about how these factors interact. There is a growing realization of the importance of environmental factors in regulating stem cell behaviour and this is being explored by imaging stem cells in vivo and recreating artificial niches in vitro. New therapies, based on stem cell transplantation or endogenous stem cells, are emerging areas, as is drug discovery based on patient-specific pluripotent cells and cancer stem cells. What makes stem cell research so exciting is its tremendous potential to benefit human health and the opportunities for interdisciplinary research that it presents.